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Review Article ISSN: 2277-8713 Priyanka Patel, IJPRBS, 2013; Volume 2(2): 430-455 IJPRBS

Available Online At www.ijprbs.com

SOLID DISPERSIONS: AN OVERVIEW TO MODIFY BIOAVAILABILITY OF POORLY

WATER SOLUBLE DRUGS

PRIYANKA PATEL, HARDIK SHAH, CHIRAG PATEL

Kalol Institute of Pharmacy, Kalol, Gujarat

Abstract

Improving oral bioavailability of drugs those given as solid dosage forms remains a challenge for the formulation scientists due to solubility problems. The dissolution rate could be the rate-limiting process in the absorption of a drug from a solid dosage form of relatively insoluble drugs. Therefore increase in dissolution of poorly soluble drugs by solid dispersion technique presents a challenge to the formulation scientists. Solid dispersion techniques have attracted considerable interest of improving the dissolution rate of highly lipophilic drugs thereby improving their bioavailability by reducing drug particle size, improving wettability and forming amorphous particles. The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic inert carrier or matrix and a hydrophobic drug. This article reviews historical background of solid dispersion technology, limitations, classification, and various preparation techniques with its advantages and disadvantages. This review also discusses the recent advances in the field of solid dispersion technology. Based on the existing results and authors’ reflection, this review give rise to reasoning and suggested choices of carrier or matrix and solid dispersion procedure.

Accepted Date:

27/03/2013

Publish Date:

27/04/2013

Keywords

Carrier;

Dissolution;

Matrix;

Poorly Soluble Drug;

Solid Dispersion;

Solubility Enhancement.

Corresponding Author

Ms. Priyanka Patel

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INTRODUCTION

An ideal drug delivery system should be

able to deliver an adequate amount of drug,

preferably for an extended period of time

for its optimum therapeutic activity. Most

drugs are inherently not long lasting in the

body and require multiple daily dosing to

achieve the desired blood concentration to

produce therapeutic activity. To overcome

such problem, controlled release and

sustained release delivery systems are

receiving considerable attention from

pharmaceutical industries worldwide. A

controlled release drug delivery system not

only prolongs the duration of action, but

also results in predictable and reproducible

drug-release kinetics. One advantage of

controlled release dosage forms is

enhanced patient compliance. Drug delivery

systems based on the principles of solid

dispersion (1). The enhancement of oral

bioavailability of poorly water soluble drugs

remains one of the most challenging

aspects of drug development. As Figure 1

indicates that salt formation, solubilization,

and particle size reduction have commonly

been used to increase dissolution rate and

thereby oral absorption and bioavailability

of such drugs, there are practical limitations

of these techniques. The salt formation is

not feasible for neutral compounds and the

synthesis of appropriate salt forms of drugs

that are weakly acidic or weakly basic may

often not be practical. Even when salts can

be prepared, an increased dissolution rate

in the gastrointestinal tract may not be

achieved in many cases because of the

reconversion of salts into aggregates of

their respective acid or base forms. The

solubilization of drugs in organic solvents or

in aqueous media by the use of surfactants

and cosolvents leads to liquid formulations

that are usually undesirable from the

viewpoints of patient acceptability and

commercialization. Although particle size

reduction is commonly used to increase

dissolution rate, there is a practical limit to

how much size reduction can be achieved

by such commonly used methods as

controlled crystallization, grinding, etc. The

use of very fine powders in a dosage form

may also beproblematic because of

handling difficulties and poor wettability.

Much of the research that has been

reported on solid dispersion technologies

involves drugs that are poorly water-soluble

and highly permeable to biological

membranes as with these drugs dissolution



is the rate limiting step to absorption.

Hence, the hypothesis has been that the

rate of absorption in vivo will be

concurrently accelerated with an increase in

the rate of drug dissolution. In the

Biopharmaceutical Classification System

(BCS) (Figure 2) drugs with low aqueous

solubility and high membrane permeability

are categorized as Class II drugs (2).

Therefore, solid dispersion technologies are

particularly promising for improving the

oral absorption and bioavailability of BCS

Class II drugs.

Oral drug delivery is the simplest and

easiest way of administering drugs (3).

Because of the greater stability, smaller

bulk, accurate dosage and easy production,

solid oral dosages forms have many

advantages over other types of oral dosage

forms. Therefore, most of the new chemical

entities (NCE) under development these

days are intended to be used as a solid

dosage form that originate an effective and

reproducible in vivo plasma concentration

after oral administration (4, 5). In fact, most

NCEs are poorly water soluble drugs, not

well-absorbed after oral administration,

which can detract from the drug’s inherent

efficacy (6, 7). Moreover, most promising

NCEs, despite their high permeability, are

generally only absorbed in the upper small

intestine, absorption being reduced

significantly after the ileum, showing,

therefore, that there is a small absorption

window (8, 9). Consequently, if these drugs

are not completely released in this

gastrointestinal area, they will have a low

bioavailability. Therefore, one of the major

current challenges of the pharmaceutical

industry is related to strategies that

improve the water solubility of drugs (10).

Drug release is a crucial and limiting step for

oral drug bioavailability, particularly for

drugs with low gastrointestinal solubility

and high permeability. By improving the

drug release profile of these drugs, it is

possible to enhance their bioavailability and

reduce side effects. Solid dispersions are

one of the most successful strategies to

improve drug release of poorly soluble

drugs. These can be defined as molecular

mixtures of poorly water soluble drugs in

hydrophilic carriers, which present a drug

release profile that is driven by the polymer

properties.

In addition to the improvement of

bioavailability, most of recent researches on

solid dispersion systems have been being



directed toward their application to the

development of extended-release dosage

forms. However several factors such as

complicated preparation method, low

reproducibility of physicochemical

properties, difficulty of formulation

development and scale-up and physical

instability for solid dispersion make it

difficult to apply the systems to solid

dispersion dosage forms. Especially in order

to maintain a supersaturation level of drug

for an extended time, re-crystallization of

drug must be prevented during its release

from dosage form (11). Dissolution

retardation through the solid dispersion

technique has become a field of interest in

recent year. Shaikh et al prepared

prolonged release solid dispersions of

acetaminophen and theophylline by a

simple evaporation method using ethyl

cellulose as water–insoluble carrier. (12).

Oral devices made to be retained in the

stomach for a long time and to ensure slow

delivery of drug above it’s absorption site,

could provide increased and more

reproducible drug bioavailability (13).

During the last decade, the sustained

release technique has been largely utilized

to obtain the controlled release of

pharmaceutical forms of both water soluble

and sparingly soluble drugs using

hydrophobic and hydrophillic polymers,

respectively. Limitations in the

development of solid dispersions were

mainly due to physical instability of these

systems. During this time phase separation

of components can occur. Furthermore,

polymeric materials are not in

thermodynamic equilibrium below their

glass transition temperatures (Tg), so the

solid polymer approaches its more stable

state (lower energy). If these

macromolecular rearrangements occur

during the experiments, a variation of the

mechanical and permeation properties of

the materials can be observed. This process

is known as ‘Physical ageing’ (14).

Figure 1. Approaches to Increase

solubility/ Dissolution



Figure 2. Biopharmaceutical Classification

System break down of the pharma new

chemical entity pipeline

ADVANTAGES OF SOLID DISPERSIONS

OVER OTHER STRATEGIES TO IMPROVE

BIOAVAILABILITY OF POORLY WATER

SOLUBLE DRUGS

Improving drug bioavailability by changing

their water solubility has been possible by

chemical or formulation approaches (15).

Chemical approaches to improving

bioavailability without changing the active

target can be achieved by salt formation or

by incorporating polar or ionizable groups in

the main drug structure, resulting in the

formation of a pro-drug. Solid dispersions

appear to be a better approach to improve

drug solubility than these techniques,

because they are easier to produce and

more applicable. For instance, salt

formation can only be used for weakly

acidic or basic drugs and not for neutral.

Furthermore, it is common that salt

formation does not achieve better

bioavailability because of its in vivo

conversion into acidic or basic forms (16).

Moreover, these type of approaches have

the major disadvantage that the sponsoring

company is obliged to perform clinical trials

on these forms, since the product

represents a NCE. Formulation approaches

include solubilisation and particle size

reduction techniques, and solid dispersions,

among others. Solid dispersions are more

acceptable to patients than solubilization

products, since they give rise to solid oral

dosage forms instead of liquid as

solubilization products usually do. Milling or

micronizations for particle size reduction

are commonly performed as approaches to

improve solubility, on the basis of the

increase in surface area. Solid dispersions

are more efficient than these particle size

reduction techniques, since the latter have

a particle size reduction limit around 2–5

mm which frequently is not enough to

improve considerably the drug solubility or

drug release in the small intestine and,

consequently, to improve the

bioavailability. Moreover, solid powders



with such a low particle size have poor

mechanical properties, such as low flow and

high adhesion, and are extremely difficult to

handle (17).

ADSORBENT CARRIER CHALLENGES

Difficult to process powders (pulverization,

poor compressibility, poor flow, scale-up)

and amorphous stability (conversion of

amorphous forms back to crystalline form)

are the major problems associated with

commercialization of this technology. Solid

powders with low particle size have poor

flowability and may stick to the tabletting

machines making it difficult to handle. The

amorphization achieved by solid dispersion

may have stability problems due to

temperature or moisture stress during

storage. Undoubtedly, the physical and

chemical properties of the carrier will

impact the bioavailability.

SOLID DISPERSIONS DISADVANTAGES

Despite extensive expertise with solid

dispersions, they are not broadly used in

commercial products, mainly because there

is the possibility that during processing

(mechanical stress) or storage (temperature

and humidity stress) the amorphous state

may undergo crystallization and dissolution

rate decrease with ageing. The effect of

moisture on the storage stability of

amorphous pharmaceuticals is also a

significant concern, because it may increase

drug mobility and promote drug

crystallization (18). Moreover, most of the

polymers used in solid dispersions can

absorb moisture, which may result in phase

separation, crystal growth or conversion

from the amorphous to the crystalline state

or from a metastable crystalline form to a

more stable structure

during storage. This may result in decreased

solubility and dissolution rate. Therefore,

exploitation of the full potential of

amorphous solids requires their

stabilization in solid state, as well as during

in vivo performance (19).

LIMITATIONS OF SOLID DISPERSION

SYSTEMS

Limitations of this technology have been a

drawback for the commercialization of solid

dispersions. The limitations include:

1. Laborious and expensive methods of

preparation,

2. Reproducibility of physicochemical

characteristics,



3. Difficulty in incorporating into

formulation of dosage forms,

4. Scale-up of manufacturing process, and

5. Stability of the drug and vehicle.

6. its method of preparation,

Various methods have been tried recently

to overcome the limitation and make the

preparation practically feasible. Some of the

suggested approaches to overcome the

aforementioned problems and lead to

industrial scale production are discussed

here under alternative strategies.

SUITABLE PROPERTIES OF A CARRIER FOR

SOLID DISPERSIONS

Following criteria should be considered

during selection of carriers: (a) High water

solubility – improve wettability and

enhance dissolution (b) High glass transition

point – improve stability (c) Minimal water

uptake (reduces Tg) (d) Soluble in common

solvent with drug –solvent evaporation (e)

Relatively low melting point –melting

process (f) Capable of forming a solid

solution with the drug-similar solubility

parameters

First generation carriers

Crystalline carriers: Urea, Sugars, Organic

acids

Second generation carriers

Amorphous carriers: Polyethyleneglycol,

Povidone, Polyvinylacetate,

Polymethacrylate, cellulose derivatives

Third generation carriers

Surface active self emulsifying carriers:

Poloxamer 408, Tween 80, Gelucire 44/14.

SOLVENT SELECTION FOR SOLID

DISPERSION SYSTEMS

In order to prepare solid dispersion,

solvents should be selected on the basis of

following criteria: (a) Dissolve both drug

and carrier (b) Toxic solvents to be avoided

due to the risk of residual levels after

preparation e.g. chloroform and

dichloromethane (c) Ethanol is a less toxic

alternative (d) Water based systems

preferable (e) Use of surfactants to create

carrier drug solutions but care should be

taken as they can reduce the glass

transition point.

Class I Solvents (Solvents to be avoided)

Solvents in Class I should not be employed

in the manufacture of drug substances,



excipients and drug products because of

their deleterious environmental effect

Table 1.

Class II Solvents (Solvents to be limited)

Solvents in Table 2 should be limited in

pharmaceutical products because of their

inherent toxicity.

Class III Solvents (Solvents with low toxic

potential)

Solvents in class III (shown in table 3) may

be regarded as less toxic and of lower risk

to human health. Class III includes no

solvents known as a human health hazard

at level normally accepted in

pharmaceuticals.

Class IV Solvents (Solvents for which no

adequate toxicological data was found)

Some solvents may also be of interest to

manufacturers of excipients, drug

substances, or drug products for example

Petroleum ether, isopropyl ether. However,

no adequate toxicological data on which to

base a PDE was found.

Table 1. List of some Class I Solvents

Solvent Concentration limit (ppm) Concern

Benzene Carbon tetrachloride 1,2-dichloroethane 1,1-dichloroethene 1,1,1-trichloroethane

2 4 5 8 1500

Carcinogen Toxic and environmental hazards Toxic Toxic Environmental hazards

Table 2. Class II solvents in pharmaceutical products

Solvent PDE (mg/day) Concentration limit (ppm)

Chlorobenzene Chloroform Cyclohexane 1,2-dichloroethene Ethylene glycol

3.6 0.6 38.8 18.7 6.2

360 60 3880 1870 620



Methanol Pyridine Toluene

30.0 2.0 8.9

3000 200 890

Table 3. Class III solvents which should be limited by GMP or other quality based

requirements

Acetic acid Acetone 1-Butanol 2-Butanol Butyl acetate Dimethylsulfoxide Ethanol Ethylacetate Ethyl ether Formic acid

Heptane Isobutyl acetate Isopropyl acetate Methyl acetate 3-Methyl-1-Butanol Pentane 1-Pentanol 1-Propanol 2-Propanol Propyl acetate

Figure 3. Solid State Solid Dispersions

Figure 4. Methods of preparation of Solid Dispersion



METHOD OF PREPARATION

Various preparation methods for solid

dispersions have been reported in

literature. These methods deal with the

challenge of mixing a matrix and a drug,

preferably on a molecular level (Figure 3),

while matrix and drug are generally poorly

miscible. During many of the preparation

techniques, de-mixing (partially or

complete), and formation of different

phases is observed. Phase separations like

crystallization or formation of amorphous

drug clusters are difficult to control and

therefore unwanted. It was already

recognized in one of the first studies on

solid dispersions that the extent of phase

separation can be minimized by a rapid

cooling procedure (20). Generally, phase

separation can be prevented by maintaining

a low molecular mobility of matrix and drug

during preparation. On the other hand,

phase separation is prevented by

maintaining the driving force for phase

separation low for example by keeping the

mixture at an elevated temperature there

by maintaining sufficient miscibility for as

long as possible. Techniques for preparation

of solid dispersions (Figure 4) are as follows:

a) Fusion method

Sekiguchi and Obi prepared solid

dispersions of sulfathiazole in such carriers

as ascorbic acid, acetamide, nicotinamide,

nicotinic acid, succinimide, and urea by

melting various drug-carrier mixtures. To

minimize melting temperatures, eutectic

mixtures of the drug with carriers were

used. Yet, in all cases, except acetamide,

the melting temperatures were >110 °C,

which could chemically decompose drugs

and carriers. High temperatures (>100 °C)

were also utilized by Goldberg et al. in

preparing acetaminophen- urea,



griseofulvin succinic acid, and

chloramphenicol- urea8 solid dispersions.

After melting, the next difficult step in the

preparation of solid dispersions was the

hardening of melts so that they could be

pulverized for subsequent

formulation into powder-filled capsules or

compressed tablets. Sekiguchi and Obi

cooled the sulfathiazole- urea melt rapidly

in an ice bath with vigorous stirring until it

solidified (21). Chiou and Riegelman

facilitated hardening of the griseofulvin-PEG

6000 solid dispersion by blowing cold air

after spreading it on a stainless steel plate

and then storing the material in a desiccator

for several days (18-19). In preparing

primidone-citric acid solid dispersions,

Summers and Enever spread the melt on

Petri dishes, cooled it by storing the Petri

dishes in a desiccator, and finally placed the

desiccator at 60 °C for several days. Allen et

al. prepared solid dispersions of

corticosteroids in galactose, dextrose, and

sucrose at 169, 185, and 200 °C,

respectively, and then placed them on

aluminum boats over dry ice. Timko and

Lordi also used blocks of dry ice to cool and

solidify phenobarbital-citric acid mixtures

that had previously been melted on a frying

pan at 170 °C. The fusion method of

preparing solid dispersion remained

essentially similar over the period of time.

More recently, Lin and Cham prepared

nifedipine- PEG 6000 solid dispersions by

blending physical mixtures of the drug and

the carrier in a V-shaped blender and then

heating the mixtures on a hot plate at 80-85

°C until they were completely melted. The

melts were rapidly cooled by immersion in a

freezing mixture of ice and sodium chloride,

and the solids were stored for 24 h in a

desiccator over silica gel before

pulverization and sieving. Mura et al.

solidified naproxen-PEG melts in an ice bath

and the solids were then stored under

reduced pressure in a desiccator for 48 h

before they were ground into powders with

a mortar and pestle. In another study,

Owusu-Ababio et al. prepared a mefenamic

acid-PEG solid dispersion by heating the

drug-carrier mixture on a hot plate to a

temperature above the melting point of

mefenamic acid (253 °C) and then cooling

the melt to room temperature under a

controlled environment (22).

b) Solvent method



Another commonly used method of

preparing a solid dispersion is the

dissolution of drug and carrier in a common

organic solvent, followed by the removal of

solvent by evaporation (23). Because the

drug used for solid dispersion is usually

hydrophobic and the carrier is hydrophilic,

it is often difficult to identify a common

solvent to dissolve both components. Large

volumes of solvents as well as heating may

be necessary to enable complete

dissolution of both components. Chiou and

Riegelman used 500 ml of ethanol to

dissolve 0.5 g of griseofulvin and 4.5 g of

PEG 6000. Although in most other reported

studies the volumes of solvents necessary

to prepare solid dispersions were not

specified, it is possible that they were

similarly large (18, 19). To minimize the

volume of organic solvent necessary, Usui

et al. dissolved a basic drug in a

hydroalcoholic mixture of 1 N HCl and

methanol, with drug-to cosolvent ratios

ranging from 1:48 to 1:20, because as a

protonated species, the drug was more

soluble in the acidic cosolvent system than

in methanol alone. Some other

investigators dissolved only the drug in the

organic solvent, and the solutions were

then added to the melted carriers. Vera et

al. dissolved 1 g of oxodipine per 150 mL of

ethanol before mixing the solution with

melted PEG 6000. In the preparation of

piroxicam-PEG 4000 solid dispersion,

Fernandez et al. dissolved the drug in

chloroform and then mixed the solution

with the melt of PEG 4000 at 70°C. Many

different methods were used for the

removal of organic solvents from solid

dispersions (23, 24). Simonelli et al.

evaporated ethanolic solvent on a steam

bath and the residual solvent was then

removed by applying reduced pressure.

Chiou and Riegelman dried an ethanolic

solution of griseofulvin and PEG 6000 in an

oil bath at 115 °C until there was no

evolution of ethanol bubbles. The viscous

mass was then allowed to solidify by cooling

in a stream of cold air. Other investigators

used such techniques as vacuum-drying,

spray-drying, spraying on sugar beads using

a fluidized bed-coating system,

lyophilization, etc., for the removal of

organic solvents from solid dispersions.

None of the reports, however, addressed

how much residual solvents were present in

solid dispersions when different solvents,

carriers, or drying techniques were used.



c) Supercritical Fluid Method

Under the influence of pressure and

temperature, pure substances can assume a

gas, liquid and solid state of matter except

where the equilibrium saturation curve

converges such that all three phases co-

exist at the triple point. Extension of the

liquid-gas phase line ends at the critical

point and represents the maximum

temperature and pressure in which the

liquid and vapor phases coexist in

equilibrium, after which gas and liquid have

the same density and appear as a single

phase. A fluid is said to be supercritical

when its temperature and pressure are in a

state above its critical temperature (Tc) and

critical pressure (Pc), permitting both

gaseous and liquid phases to co-exist. The

most important property of supercritical

fluid is the liquid-like density, large

compressibility and viscosity intermediate

between the gas and liquid extremes. Large

density cannotes solvent power whereas

high compressibility affords a strategy for

continuously adjusting this solvent power

between gas and liquid like extremes with

small changes of pressure 25. Because

density is the true measure of a

supercritical fluid’s solvent power, small

changes in temperature and pressure can

result in large changes in solubility.

Supercritical fluids are typically hundreds of

times denser than gases at ambient

conditions but are arbitrarily more

compressible. Compressibility is the

fundamental degree of freedom, absent

with conventional solvents but present with

supercritical fluids, and gives rise to their

key feature as a pharmaceutical solvent:

small changes in pressure cause large

changes in density (26, 27). Thus, by

manipulating only pressure and

temperature, the formulator may control

solubility in a coacervation process.

Supercritical carbon dioxide (critical

pressure and temperature of about 1070 psi

and 310C, respectively) has induced dipole

and quadruple interactions that dissolve

non-polar to moderately polar

compounds6. Recent reports describe the

use of carbon dioxide near its critical

temperature and pressure to partially

solvate polymers and infuse small drug

molecules into their swollen networks for

controlled release applications. The

mechanism by which supercritical carbon

dioxide mixtures achieve this effect

originates, in part, from its ability to



dissolve drug molecules but also their

ability to function as theta solvent thereby

swelling polymer matrices to permit drug

loading. This approach provides advantages

over conventional, unit operations (eg.

Freeze drying or spray drying), which are

typically heat and time intensive.

Supercritical fluid processing (SFP) is rapid,

characterized by high purity product and

high yield due to ease of solvent removal.

Because aqueous solvents are not

employed in SFP, the Stability of

pharmaceuticals susceptible to hydrolytic

degradation may be enhanced. Compared

with other non-aqueous alternatives,

carbon dioxide is generally regarded as safe

as a pharmaceutical excipient, inexpensive

and residual free at room temperature and

atmospheric pressure, yet supercritical

under benign temperatures and tractable

pressures. SFP has been used as an

alternative to milling to generate drug

particles of narrow size distribution, to

produce polymer-drug composites or to

coat surfaces. SFP normally employs carbon

dioxide either as a solvent or anti-solvent,

in which case the process is referred to as

the rapid expansion of supercritical fluid

solutions or supercritical anti-solvent,

respectively. Rapid expansion of

supercritical fluid solutions (RESS) produces

pure drug particles several nanometers in

diameter when supercritical solutions

expand through a very small nozzle under

controlled temperature and pressure. This

technique is extremely attractive because

small particles enhance dissolution rate and

bioavailability due to their increased surface

area. However, the advantages of RESS

processing of drug-in-polymer composites

are offset by problems with clogged nozzle

heads, low drug/polymer solubilities in SF,

and congealing due to insufficiently dried

product. These problems are, to various

degrees, avoided by the supercritical anti-

solvent (SAS) process that produces dried

composites suitable for subsequent milling.

However, this process invariably requires

the use of co-solvent(s) to modify the non-

polar supercritical milieu to more polar

environment compatible with drug

substance, essentially offsetting the

intrinsic advantages of SF (28).

COMBINATION OF SOLID DISPERSION

WITH SUSTAINED RELEASE TECHNIQUES

A combination of solid dispersion and

sustained release techniques is one of the



attractive approaches since super

saturation of the drugs can be achieved by

applying solid dispersion. However, it has

been known that the super saturation level

is decreased by contacting solid dispersion

to water for a longer period because of

recrystallization of drugs. That is why only

few reports on the application of solid

dispersion to sustained release system have

been presented. One approach is direct

modification of character of solid dispersion

by using water-insoluble or slower

dissolving carriers instead of conventional

hydrophilic polymers. In this technique, a

selection of suitable carrier for each drug

would be a critical factor. Another approach

is a membrane controlled sustained release

tablet containing solid dispersion. Since the

release of drug from such a diffusion-

controlled system is driven by the gradient

of the drug concentration resulting from

penetration of water, it may have the risk

for the re-crystallization of the drug

because of contacting solid dispersion to

water penetrated into the system for longer

period. Therefore, a specific formula of solid

dispersion and/or a manufacturing method

may be required for each drug depending

on the character of the drug in order to

maintain the supersaturation.

RECRYSTALLIZATION: STRATEGIES TO

AVOID IT

Recrystallization is the major disadvantage

of solid dispersions. As amorphous systems,

they are

Thermodynamically unstable and have the

tendency to change to a more stable state

under recrystallization. Molecular mobility

is a key factor governing the stability of

amorphous phases, because even at very

high viscosity, below the glass transition

temperature (Tg), there is enough mobility

for an amorphous system to crystallize over

pharmaceutically relevant time scales.

Furthermore, it was postulated that

crystallization above Tg would be governed

by the configurational entropy, because this

was a measure of the probability of

molecules being in the appropriate

conformation, and by the mobility, because

this was related to the number of collisions

per unit time. Several experiments have

been conducted to understand the

stabilization of solid dispersions. Recent

studies observed very small reorientation

motions in solid dispersions showing a



detailed heterogeneity of solid dispersions

and detecting the sub-glass transition beta-

relaxation as well as alpharelaxation, which

may lead to nucleation and crystal growth.

Molecular mobility of the amorphous

system depends; not only on its

composition, but also on the manufacturing

process as stated by Bhugra et al. Solid

dispersions exhibiting high conformational

entropy and lower molecular mobility are

more physically stable (29). Polymers

improve the physical stability of amorphous

drugs in solid dispersions by increasing the

Tg of the miscible mixture, thereby reducing

the molecular mobility at regular storage

temperatures, or by interacting specifically

with functional groups of the drugs. For a

polymer to be effective in preventing

crystallization, it has to be molecularly

miscible with the drug. For complete

miscibility, interactions between the two

components are required. It is recognized

that the majority of drugs contain

hydrogen-bonding sites, consequently,

several studies have shown the formation

of ion–dipole interactions and

intermolecular hydrogen bonding between

drugs and polymers, and the disruption of

the hydrogen bonding pattern characteristic

to the drug crystalline structure. These lead

to a higher miscibility and physical stability

of the solid dispersions (30, 31). Specific

drug polymer interactions were observed

by Teberekidis et al., showing that

interaction energies, electron density, and

vibrational data revealed a stronger

hydrogen bond of felodipine with PVP than

with PEG, which was in agreement with the

dissolution rates of the corresponding solid

dispersions. Other studies have shown

stabilization in systems where hydrogen-

bonding interactions are not possible,

because of the chemistry of the system.

Vippagunta et al. concluded that

fenofibrate does not exhibit specific

interactions with PEG, independent of the

number of hydrogen bonds donating groups

presented. The same conclusion was

achieved by Weuts et al. in the preparation

of solid dispersions of loperamide with PVP

K30 and PVP VA64, in which, hydrogen

bonds were no absolute condition to avoid

crystallization. Konno et al. determined the

ability of three different polymers, PVP,

HPMC and

Hydroxypropylmethylcellulose acetate

succinate to stabilize amorphous felodipine,

against crystallization. The three polymers



inhibited crystallization of amorphous

felodipine by reducing the nucleation rate.

It was speculated that these polymers affect

nucleation kinetics by increasing their

kinetic barrier to nucleation, proportional

to the polymer concentration and

independent of the polymer physiochemical

properties. The strategies to stabilize the

solid dispersions against recrystallization

strongly depend on the drug properties and

a combination of different approaches

appears to be the best strategy to

overcome this drawback. Third generation

solid dispersions intend to connect several

strategies to overcome the drug

recrystallization, which has been the major

barrier to the solid dispersions marketing

success (32).

CHARACTERIZATION OF SOLID

DISPERSIONS

Characterization of polymorphic and

solvated forms involves quantitative

analysis of these different physicochemical

properties. Several methods for studying

solid dosage forms are listed in Table 4

along with the sample requirements for

each test. Many attempts have been made

to investigate the molecular arrangement in

solid dispersions. However, most effort has

been put into differentiate between

amorphous and crystalline material.

For that purpose many techniques are

available which detect the amount of

crystalline material in the dispersion. The

amount of amorphous material is never

measured directly but is mostly derived

from the amount of crystalline material in

the sample. The properties of a solid

dispersion are highly affected by the

uniformity of the distribution of the drug in

the matrix. The stability and dissolution

behaviour could be different for solid

dispersions that do not contain any

crystalline drug particles.

Techniques to explore molecular

interactions and behaviour

Drug –carrier miscibility

Hot stage microscopy

DSC (Conventional modulated)

pXRD (Conventional and variable temp)

NMR 1H Spin lattice relaxation time

Drug carrier interactions

FT-IR spectroscopy



Raman spectroscopy

Solid state NMR

Physical Structure

Scanning electron microscopy

Surface area analysis

Surface properties

Dynamic vapor sorption

Inverse gas chromatography

Atomic force microscopy

Raman microscopy

Amorphous content

Polarised light optical microscopy

Hot stage microscopy

Humidity stage microscopy

DSC (MTDSC)

ITC

pXRD

Stability

Humidity studies

Isothermal calorimetry

DSC (Tg, Temperature recrystallization)

Dynamic vapor sorption

Saturated solubility studies

Dissolution enhancement

Dissolution

Intrinsic dissolution

Dynamic solubility

Dissolution in bio-relevant media

PHYSICAL STABILITY OF AMORPHOUS

SOLID DISPERSIONS

The dissolution behaviour of solid

dispersions must remain unchanged during

storage. The best way to guarantee this is

by maintaining their physical state and

molecular structure. For optimal stability of

amorphous solid dispersions, the molecular

mobility should be as low as possible.

However, solid dispersions, partially or fully

amorphous, are themodynamically

unstable. In solid dispersions containing

crystalline particles, these particles form

nuclei that can be the starting point for

further crystallization. It has been shown

that such solid dispersions show

progressively poorer dissolution behaviour



during storage [33, 34]. In solid dispersions

containing amorphous drug particles, the

drug can crystallize, but a nucleation step is

required prior to that. In homogeneous

solid dispersions, the drug is molecularly

dispersed, and crystallization requires

another step. Before nucleation can occur,

drug molecules have to migrate through the

matrix. Therefore, physical degradation is

determined by both diffusion and

crystallization of drug molecules in the

matrix. It should be noted that in this

respect it is better to have a crystalline

matrix, because diffusion in such a matrix is

much slower. Physical changes are depicted

in figure 5.

The physical stability of amorphous solid

dispersions should be related not only to

crystallization of drug but to any change in

molecular structure including the

distribution of the drug. Moreover, the

physical state of the matrix should be

monitored, because changes therein are

likely to alter the physical state of the drug

and drug release as well.

DRUG-MATRIX MASS RATIO

Several aspects determine the effect of

amorphous solid dispersion composition on

physical stability. Firstly, the diffusion

distance for separate drug molecules to

form amorphous or crystalline particles is

larger for lower drug contents. Hence, the

formation of a separate drug phase is

significantly retarded. Secondly, low drug

contents minimize the risk of exceeding the

solid solubility [35, 38]. When the solid

solubility is lower than the drug load, there

is a driving force for phase separation. This

is only relevant for drug-matrix

combinations that are partially miscible or

immiscible. Thirdly, the Tg of a

homogeneous solid dispersion is a function

of the composition. When the drug has a

lower Tg than the matrix, a high drug

content depresses the Tg of the solid

dispersion, increasing the risk for phase

separation. And finally, if drug-matrix

interaction increases stability, then also low

drug contents are preferred, since in that

case drug-drug contacts will be rare and

drug-matrix contacts omnipresent. These

arguments favour the choice of low drug

content. However, a high drug content can

decrease the hygroscopicity of the solid

dispersion and enables the preparation of a

high dosed dosage forms. The drug,

hygroscopic than the matrix. Molecularly



incorporated drug reduces the amount of

water that can plasticize the solid

dispersion when exposed to a particular

relative humidity, thereby decreasing

molecular mobility [36, 37, 40]. Therefore,

more drug can not only reduce the Tg of the

dry solid dispersion but also decrease the

plasticizing effect of water. Which one of

the two competing effects has a larger

contribution is difficult to predict. A second

reason for increased stability with

increasing drug loads is the inhibition of

crystallization of the matrix above a certain

drug load, when drug molecules sterically

block the migration of matrix molecules

[39]. Table 5 summarizes the effects of an

increased drug load.

FUTURE PROSPECTS

Solid dispersion has great potential both for

increasing the bioavailability of drug and

developing controlled release preparations.

In regard to manufacturing considerations

the problem of total solvent removal in

dispersions prepared by solvent method

needs to be addressed [41]. The method

created by Hasegawa et al that involves

spray – coating of nanoparticles or any

other inert core with drug carrier solution,

provides a one step process of achieving a

multiunit dosage form of solid dispersion.

With particle – coating equipment new

commercially available, this process has a

promising future, as exemplified by

commercial success of sporanox capsule

manufactured by this technique. The

problem of instability of the supersaturated

state upon dissolution, which results in a

stable form, has been dealt with by addition

of a retarding agent. Methylcellulose used

as a retarding agent in dispersions of

indomethacin and flufenamic acid in PVP

[42]. Controlled release formulations of

acetaminophen, aminopyrine,

chlorpheniramine maleate and salicylic acid

that use eudragit RS as a water insoluble

carrier prepared by solvent method, have

been reported. Valuable preliminary studies

of the use of solid dispersions to provide

sustained - release or controlled - release of

drugs have been reported. A U.S. patent

describes a method of preparation for a

controlled release preparation of

cyclosporine in biodegradable polymer such

as poly–D, L-lactide, or a blend of poly-D, L-

lactide and poly-D, L lactide- co-glycolide. A

novel approach that uses a less soluble

derivative of drug as a carrier was used by



Yang and Swarbrick to prepare sustained

release solid dispersion of dapsone [43].

Some example of Solid dispersions in

Market

Sporanox® (itraconazole)

Intelence® (etravirine)

Prograf® (tacrolimus)

Crestor® (rosuvastatin)

Gris-PEG® (griseofulvin)

Cesamet® (nabilone)

Solufen® (ibuprofen)

CONCLUSION

Solid dispersions can increase dissolution

rate of drugs with poor water-solubility but

stability of these systems needs

consideration. Physical and chemical

stability of both the drug and the carrier in

a solid dispersion are major developmental

issues, as exemplified by the recent

withdrawal of ritonavir capsules from the

market, so future research needs to be

directed to address various stability issues.

Solid dispersions can improve their stability

and performance by increasing drug-

polymer solubility, amorphous fraction,

particle wettability and particle porosity.

Moreover, new, optimized manufacturing

techniques that are easily scalable are also

coming out of academic and industrial

research. Further studies on scale up and

validation of the process will be essential.

Table 4. Analytic method for characterization of solid forms

Method Material required per sample

Microscopy Fusion methods (Hot stage microscopy) Differential scanning calorimetry (DSC/DTA) Infrared spectroscopy X-Ray powder diffraction (XRD) Scanning Electron Microscopy Thermogravimetric analysis Dissolution/Solubility analysis

1 mg 1 mg 2-5 mg 2-20 mg 500 mg 2 mg 10 mg mg to gm



REFERENCES

1. Iqbal, Z.; Babar, A.; Muhammad, A.

Controlledrelease Naproxen using

micronized Ethyl Cellulose by wet-

granulation and solid dispersion method.

Drug Dev. Ind. Pharm. 2002, 28 (2), 129-

134.

2. Amidon, G. L.; Lennernas, H.; Shah, V.

P.; Crison, J. R. Theoretical basis for a

biopharmaceutical drug classification: the

correlation of in vitro drug product

dissolution and in vivo bioavailability.

Pharm Res. 1995, 12 (3), 413-420.

3. Anguiano-Igea, S.; Otero-Espinar, F. J.;

Vilajato, J. L.; Blanco-mendez, J. The

properties of solid dispersions of clofibrate

in polyethylene glycols. Int. J. Pharm. 1995,

70, 57–66.

4. Serajuddin, A. T. Solid dispersion of

poorly water-soluble drugs: early promises,

subsequent problems, and recent

breakthroughs. J. Pharm. Sci. 1999, 88,

1058–1066.

5. Craig, D. Q. M. The mechanisms of drug

release from solid dispersions in water-

soluble polymers. Int. J. Pharm. 2002, 231,

131–144.

6. Chiou, W.L.; Riegelman, S.

Pharmaceutical applications of solid

dispersion systems. J. Pharm. Sci. 1971, 60,

1281–1302.

7. Matsumoto, T.; Zografi, G. Physical

properties of solid molecular dispersions of

indomethacin with poly(vinylpyrrolidone)

and poly(vinylpyrrolidone-co-vinylacetate)

in relation to indomethacin crystallization.

Pharm. Res. 1999, 16, 1722–1728.

8. Van den Mooter, G. Evaluation of Inutec

SP1 as a new carrier in the formulation of

solid dispersions for poorly soluble drugs.

Int. J. Pharm. 2006, 316, 1–6.

9. Tanaka, N. Development of novel

sustained release system, disintegration-

controlled matrix tablet (DCMT) with solid

dispersion granules of nilvadipine. J. Contr.

Release. 2005, 108, 386– 395.

10. Kimura, T.; Tanaka, N.; Imai, K.;

Okimoto, K.; Ueda, S.; Tokunaga, Y.; Ibuki,

R.; Higaki, K. Development of novel

sustained-release system, disintegration


dispersion granules of Nilvadipine (II): In



vivo evaluation. J. Control Release. 2006,

112, 51-56.

11. Dangprasirt, P.; Pongwai S.

Development of Diclofenac Sodium

controlled-release solid dispersion powders

and capsules by Freeze drying technique

using Ethyl Cellulose and Chitosan as

carriers. Drug Dev. Ind. Pharm. 1998, 24

(10), 947-9.

12. Lannuccelli, V.; Coppi, G.; Leo, E.;

Fontana, F.; Bernabei, M. T. PVP solid

dispersions for the controlled-release of

Furosemide from a floating multiple-unit

system. Drug Dev. Ind. Pharm. 2000, 26 (6),

595-603.

13. Lovrecich, M.; Nobile, F.; Rubessa, F.;

Zingone, G. Effect of ageing on the release

of Indomethacin from solid dispersions with

Eudragit. Int. J. Pharm. 1996, 131, 247-255.

14. Huang, J. Nifedipine solid dispersion in

microparticles of ammonio methacrylate

copolymer and ethylcellulose binary blend

for controlled drug delivery: Effect of drug

loading on release kinetics. Int. J. Pharm.

2006, 319, 44– 54.

15. Tanaka, N. Development of novel

sustainedrelease system, disintegration-


dispersion granules of nilvadipine (II): In

vivo evaluation. J. Contr. Release. 2006,

112, 51–56.

16. Van Drooge, D.J. Characterization of the

molecular distribution of drugs in glassy

solid dispersions at the nano-meter scale,

using differential scanning calorimetry and

gravimetric water vapour sorption

techniques. Int. J. Pharm. 2006, 310, 220–

229.

17. Kanig, J.L. Properties of Fused Mannitol

in Compressed Tablets. J. Pharm. Sci. 1964,

53, 188–192

18. Chiou, W. L.; Riegelman, S. Preparation

and dissolution characteristics of several

fast-release solid dispersions of griseofulvin.

J. Pharm. Sci. 1969, 58, 1505–1510.

19. Chiou, W. L.; Riegelman, S.

Pharmaceutical applications of solid

dispersion systems. J. Pharm. Sci. 1971, 60

(9), 1281-1302.

20. Karavas, E. Application of PVP/HPMC

miscible blends with enhanced

mucoadhesive properties for adjusting drug

release in predictable pulsatile



chronotherapeutics. Eur. J. Pharm.

Biopharm. 2006, 64, 115–126.

21. Hasegawa, S. Effects of water content

in physical mixture and heating

temperature on crystallinity of troglitazone-

PVP K30 solid dispersions prepared by

closed melting method. Int. J. Pharm. 2005,

302, 103–112.

22. Van den Mooter, G. Physical

stabilisation of amorphous ketoconazole in

solid dispersions with polyvinylpyrrolidone

K25. Eur. J. Pharm. Sci. 2001, 12, 261–269.

23. Ahuja, N. Studies on dissolution

enhancement and mathematical modeling

of drug release of a poorly water-soluble

drug using water-soluble carriers. Eur. J.

Pharm. Biopharm. 2007, 65, 26– 38.

24. Paulaitis, M. M. Solid solubilities in

supercritical fluids at elevated pressure.

Rev. Chem. Eng. 1983, 1, 179-188.

25. Palakodaty, S.; York, P. Phase

behavioural effects on particle formation

processes using supercritical fluids. Pharm.

Res. 1999, 16, 976- 980.

26. Debenedetti, P. G.; Kumar, S. K. The

molecular basis of temperature effects in

supercritical extraction. Al Chem EJ. 1998,

34, 1211.

27. Dobbs, J. M.; Wong, J. M.; Johnston,

K.P. Nonpolar co-solvents for solubility

enhancement in supercritical fluid carbpn

dioxide. J. chem. Eng. Data. 1986, 37, 303-

308.

28. A. H. Goldberg, M. Gibaldi, and J. L.

Kanig, “Increasing dissolution rates and

gastro intestinal absorption of drugs via

solid solutions and eutectic mixtures II.

Experimental evaluation of eutectic

mixture: Urea-acetaminophen system,” J.

Pharm. Sci., vol. 55, issue 5, 1966, pp. 482-

487

29. Craig, D. Q. M. Polyethylene glycols and

drug release. Drug Dev. Ind. Pharm. 1990,

16, 2501– 2527.

30. Gupta, M. K.; Goldman, D.; Bogner, R.

H.; Tseng, Y. C. Enhanced drug dissolution

and bulk properties of solid dispersions

granulated with a surface adsorbent. Pharm

Dev Tech. 2001, 6, 563-72.

31. Gupta, M. K.; Bogner, R. H.; Goldman,

D.; Tsend, Y. C. Mechanism for further

enhancement in drug dissolution from



soliddispersion granules upon storage.

Pharm Dev Tech. 2002, 7, 103-12.

32. Gupta, M. K.; Tseng, Y. C.; Goldman, D.;

Bogner, R. H. Hydrogen bonding with

adsorbent during storage governs drug

dissolution from solid-dispersion granules.

Pharm Res. 2002, 11, 1663-72.

33. Swarbrick, J.; Boylan, J. C. Encyclopedia

of Pharmaceutical Technology, 2nd edn;

Marcel Dekker Inc. Vol. I, 2002, 811-832,

641-647.

34. Serajuddin ATM, Sheen PC, Mufson D,

Bernstein DF and Augustine MA (1988).

Effect of vehicle amphiphilicity on the

dissolution and bioavailability of a poorly

water soluble drug from solid dispersions. J.

Pharm. Sci., 77: 414-417.

35. Sertsou G, James Butler, Andy Scott,

John Hempenstall and Thomas Rades

(2002). Factors affecting incorporation of

drug into solid solution with HPMCP during

solvent change co-precipitation. Int. J.

Pharm., 245(1-2): 99-108.

36. Sethia S and Squillante E (2002).

Physicochemical characterization of solid

dispersions of carbamazepine formulated

by supercritical carbon dioxide and

conventional solvent evaporation method.

J. Pharm. Sci., 91(9): 1948-1957.

37. Sethia S and Squillante E (2003). Solid

dispersions: revival with greater possibilities

and applications in oral drug delivery. Crit.

Rev. Ther. Drug Carrier Syst., 20(2-3): 215-

247.

38. Sheen PC, Khetarpal VK, Cariola CM and

Rowlings CE (1995). Formulation studies of

a poorly water-soluble drug in solid

dispersions to improve bioavailability. Int. J.

Pharm., 118: 221-227.

39. Sheen PC, Kim SI, Petillo JJ and

Serajuddin ATM (1991). Bioavailability of a

poorly water-soluble drug from tablet and

solid dispersion in humans. J. Pharm. Sci.

80: 712-714.

40. Simonelli AP, Mehta SC and Higuchi WI

(1969). Dissolution rates of high energy

polyvinylpyrrolidone (PVP)-sulfathiazole

coprecipitates. J. Pharm. Sci., 58(5): 538-

549.

41. Singh P, Leslie Z. Benet, V. N. Bhatia, J.

Keith Guillory and Theodore D. Sokoloski

(1966). Effect of inert tablet ingredients on

drug absorption. I. Effect of polyethylene

glycol 4000 on the intestinal absorption of



four barbiturates. J. Pharm. Sci., 55(1): 63-

68.

42. Sjokvist E, Nystrom C, Alde´n M and

Caram-Lelham N (1992). Physicochemical

aspects of drug release. XIV. The effects of

some ionic and nonionic surfactants on

properties of a sparingly soluble drug in

solid dispersions. Int. J. Pharm., 79: 123-

133.

43. Slade L and Levine H (1991). A food

polymer science approach to

structureproperty relationships in aqueous

food systems: non-equilibrium behavior of

carbohydrate-water systems, in Water

relationships in food, H. Levine and L. Slade,

Editors. Plenum Press: New York, pp.29-

101.

44. Subramaniam B, Rajewski RA and

Snavely K (1997). Pharmaceutical

processing with supercritical carbon

dioxide. J. Pharm. Sci., 86(8): 885-890.

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